Gene therapy has been investigated for delivery of therapeutic genes to the CNS cells for treatment of various CNS disease, e.g., Canavan disease, ALS, Parkinson disease (PD), etc. In some limited cases, therapeutic benefits have been observed using certain viruses, e.g., recombinant adenovirus (rAd), lentivirus (LV) and adeno-associated virus (AAV) to express a variety of therapeutic genes. AAV2 has been used in clinical trials for treatment of PD and Leber congenital amaurosis (an eye disease) and preliminary findings suggest symptomatic improvements without noticeable toxicity [2-4].
However, AAV-based gene therapy to treat CNS disease has still faced major obstacle. Many CNS diseases including, for example, ALS affect both cortical and spinal motor neurons that are distributed in a very broad area in the CNS. It has frequently been the case that viral vectors injected into CNS tissue transduce cells only in the vicinity of the injection site, have a very limited spread and generally have not impacted the lifespan in CNS disease animal models [See, e.g., Ref. 5]. Still, a variety of other viral administration methods have been tested. One example, involves injecting the viral particles into skeletal muscle and allowing the nerve terminals to internalize the viral genome, which is then retrogradely transported back to the spinal motor neurons. This approach has shown some positive results in certain mouse models [68]. However, to apply this method in larger mammals, like adult humans, would be impractical. Overall, the transduction efficiency observed with muscle injection is relatively low. Some investigators have tried to improve this efficiency by modifying viral capsid proteins with the nerve binding domains of tetanus toxin or botulinum toxin. These efforts have not been fruitful due to various technical difficulties. Another problem with muscle injection in larger mammals, is a need for large doses, which is technically challenging, expensive, and carries a high risk for adverse effects, ranging from immune reaction to transduction of unintended cells (e.g., germ cells).
Another method that has been evaluated for delivering transgenes into motor neurons is to inject the virus into large nerves, which maximizes that exposure of the virus to motor axons, allowing the motor neurons to internalize the viral genome and retrogradely transport them back to the cell body. This method has been demonstrated to be more efficient in transducing motor neurons than muscle injection [9]. Still, to implement a method such as this in larger mammals would be challenging.